The broad goal of this proposal is to determine the effect of aging on areas of the brain whose function is impacted by gonadal steroids in women. The overarching hypothesis is that aging differentially alters the effects of estrogens on the brain. In this proposal we will focus on the impact of aging on changes in cortical function induced by estrogen in areas of the brain associated with verbal working memory and declarative/episodic memory. We will use postmenopausal women as our model as the absence of gonadal function makes it possible to control the duration and amount of estrogen exposure. We will investigate the effects of both short-term (48 hr) and prolonged (30 days) estrogen exposure in young women with premature menopause (< 40) and in young (45-55) and old (70-80) postmenopausal women to determine whether the changes in brain regions involved in cognition that we have seen with short-term estrogen exposure persist with prolonged exposure, a finding that would have tremendous clinical relevance. In Aim 1 we will use [18F] 2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) to address the hypotheses that resting state metabolic activity is decreased with aging at baseline in the dorsolateral prefrontal cortex (DLPFC) and hippocampus; that estrogen exposure results in progressive increases in resting metabolic activity in the DLPFC over time in women with premature menopause and in young postmenopausal women that is not seen in their older counterparts; and that estrogen exposure results in differential changes in resting metabolic activity in the hippocampus as a function of aging. In Aim 2 we will use functional magnetic resonance imaging (fMRI) to determine the effect of aging on cortical activation to address the hypotheses that activation during specific tasks of working memory is lower at baseline in the DLPFC, but higher in the hippocampus in older compared with younger menopausal women; and that estrogen exposure results in a progressive increase in activation of the DLPFC during working memory tasks over time in younger, but not older, menopausal women. These studies will provide critical insights into the interaction between reproductive hormones and aging on areas of the brain involved in cognition in women, providing information that is critical to the clinical management of women with reproductive disorders and following cessation of reproductive function. Abstract R01 AG13241-A2 Janet E. Hall, MD PUBLIC HEALTH RELEVANCE: Cognitive function is affected by both aging and the loss of estrogen that is associated with the menopause. In this proposal we will use sophisticated neuroimaging tools to examine the interaction between aging and estrogen on areas of the brain that are involved in memory. This information will be critical for optimizing quality of life for the millions of women who now spend a third of their lives after menopause.